european hematology association

European Hematology AssociationINVESTOR PRESENTATION

JUNE 11, 2021

1

Legal Disclaimer

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This presentation contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation,

express or implied statements regarding the company’s beliefs and expectations regarding its: business plans and objectives; future plans for etavopivat (FT-4202), FT-7051 and

olutasidenib, including expectations regarding timing and success of the current ongoing clinical trials, therapeutic potential, clinical benefits and safety thereof, planned

regulatory submissions, including a new drug application (NDA) for olutasidenib, and upcoming milestones for the company’s other product candidates; growth as a company;

presentation of additional data at upcoming scientific conferences, and other preclinical data and potential data publications in 2021; the potential commercial and collaboration

opportunities, including potential future collaborators and parties, as well as value and market, for our product candidates; uses and need of capital, expenses and other 2021

financial results currently or in the future, and the potential impact of COVID-19 on patient retention and enrollment, future operations, clinical trials or investigational new drug

(IND) applications. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target”

and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words.

Any forward-looking statements in this presentation are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and

important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this presentation,

including, without limitation, those risks and uncertainties associated with the following: the impact of the COVID-19 pandemic on the company’s business, operations, patient

enrollment and retention , strategy, goals and anticipated milestones; the therapeutic potential of etavopivat, FT-7051, and olutasidenib, and the timing associated with the

initiation or continuation of any trials and success of ongoing clinical trials of etavopivat and FT-7051; Forma’s ability to execute on its strategy; the submission and acceptance of

an NDA for submission to the U.S. Food and Drug Administration (FDA) for olutasidenib; positive results from a clinical study may not necessarily be predictive of the results of

future or ongoing clinical studies; any one or more of Forma’s product candidates may not be successfully developed and commercialized; regulatory developments in the United

States and foreign countries; Forma’s ability to protect and maintain our intellectual property position; the impact of COVID-19 affecting countries or regions in which we have

operations or do business, including potential negative impacts on our employees, customers, supply chain and production as well as global economies and financial markets;

Forma’s ability to fund operations; Forma’s ability to identify satisfactory collaboration opportunities, as well as those risks and uncertainties set forth more fully under the caption

"Risk Factors" in our quarterly report on form 10-Q for the period ended March 31, 2021 filed with the United States Securities and Exchange Commission (SEC) and subsequent

filings with the SEC. Forma disclaims any obligation to publicly update or revise any such statements to reflect any change in expectations or in events, conditions or

circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements.

Any forward-looking statements contained in this presentation represent Forma’s views only as of the date hereof and should not be relied upon as representing its views as of

any subsequent date. Forma explicitly disclaims any obligation to update any forward-looking statements.

Meeting Agenda

FORMA THERAPEUTICS OVERVIEW

Frank D. Lee, President, CEO and Director

ETAVOPIVAT RESULTS PRESENTATION

Patrick Kelly M.D., Chief Medical Officer

David Cook, Ph.D. Chief Scientific Officer

QUESTION AND ANSWER

R. Clark Brown, M.D., Ph.D., Associate Professor Of Pediatrics, Emory University School Of Medicine

Medical Director Of Sickle Cell At Scottish Rite, Aflac Cancer And Blood Disorders Center Of Children's Healthcare Of Atlanta

Marilyn J. Telen, M.D., Wellcome Professor Of Medicine, Division Of Hematology

Director, Duke Comprehensive Sickle Cell Center

MEETING SUMMARY AND CLOSE

Frank D. Lee, President, CEO and Director

3

1

2

3

4

Frank LeePRESIDENT, CHIEF EXECUTIVE OFFICER,

AND DIRECTOR

4

Transforming the lives of patients with

rare hematologic diseases and cancers

Forma Therapeutics’ pipeline

6

PROGRAM

(TARGET) INDICATION

DEVELOPMENT STAGE

COMMERCIAL

RIGHTS RECENT EVENTSPRECLINICAL PHASE 1 PHASE 2 PHASE 3

Etavopivat

(PKR)

Sickle Cell

Disease

• Presented Phase 1 SCD data at EHA/ASH

• Ongoing Phase 1 SCD MAD/OLE

• Initiated Phase 2/3 pivotal trial (Hibiscus Study)

Thalassemia

FT-7051 (CBP/p300)

mCRPC• Cleared IND application

• Initiated Phase 1 trial

Olutasidenib

(IDH1m)

AML• NDA-enabling Phase 2 IA2 completed in R/R AML

• Presented Phase 2 AML data at ASCO 2021

Glioma • Presented Phase 1 trial, 12-month data at ASCO 2020

FT-8225

(FASN)NASH

CC-95775

(BET)NHL

B1-1701963

(KRAS)Solid Tumors

AML, acute myeloid leukemia; BET, bromodomain and extra-terminal; CBP/p300, BREN binding protein/p300; FASN, fatty acid synthase; IA2, interim analysis 2; IND, investigational new drug;

IDH1m, isocitrate dehydrogenase 1 mutations; mCRPC, metastatic castration-resistant prostate cancer; NASH, nonalcoholic steatohepatitis, NHL, non-Hodgkin's lymphoma; PKR, pyruvate kinase-R

Potential timelines and milestones

7FPI, first patient in; IA, interim analysis; MAD, multiple ascending dose; NTD, non-transfusion dependent; OLE, open label extension; TD, transfusion-dependent

PHASE 2: DOSE SELECTION

PHASE 1

EHASingle dose SCD

ASHMAD1 300mg

EHA12 week OLE

Initial results

ASCOPhase 1 data

ETAVOPIVAT: SCD

FT-7051: mCRPC

PHASE 3: EFFICACY

CONTINUATION

IA#1 (12 weeks)Dose Selection

FDA Type C

IND

MAD2 600mg

FPI

PHASE 1 SINGLE DOSE/MAD/OLE

ETAVOPIVAT: THALASSEMIA (TD/NTD) PHASE 2

ASHFinal OLE Results

PEDIATRIC SCD

2020 2021 2022

ASCO GUAACR-NCI-EORTC

Significant unmet needs remain in SCD

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Prevalence

~100KSCD patients in the US

~1 in 365 Black Americans affected

at birth

25-30yrReduction in

average life expectancy

Symptoms

May include anemia, inflammation,

and painful vaso-occlusive crises

~55%Days with pain

↑Risk ofStroke

Acute Chest Syndrome

Renal failure

Sources: Evaluate Report Sickle cell disease by country accessed February 03, 2020. Smith WR, et al. Ann Intern Med. 2008;148:94–101. Lanzkron S, et al. Pub Health Rep.

2013;128:110-116. Ballas, S.K. American Journal of Hematology DOI: 10.1002/ajh.21443. Centers for Disease Control and Prevention. Sickle cell disease (SCD) accessed May 4, 2021.

Treatments

~50%>1 g/dL inc. in Hb

or

~1VOC improvement per yr

(From 3 to 2 VOCs/yr)

y

Etavopivat is a potential foundational, disease-modifying therapy

Granted FDA Fast Track and Rare Pediatric, Orphan Drug designations

Multi-modal MoA ↓2,3-DPG and ↑ATP

Potential to improve both hemoglobin levels and VOCs

Improves RBC health and functions important to metabolic health, adhesion, and survival

Oral, once daily tablet-Low risk of drug-drug interactions; no aromatase inhibition properties;

does not autoinduce its own metabolism

Granted Fast Track, Rare Pediatrics and Orphan designations

✓

✓

✓

✓

9

✓

Patrick Kelly, M.D.SVP, CHIEF MEDICAL OFFICER

10

Etavopivat Phase 1 DataAnalysis as of May 2021

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12

Etavopivat-mediated PKR Activation: Sickle RBC Health and FunctionMultimodal MOA: Increase Hb and Decrease VOC

GLUCOSE

Hb

Deoxy-Hb

PYRUVATE

ATP

ADP

PEP

2,3-DPG

PKREtavopivat

HbS polymerization

RBC membrane integrity

ANTICIPATED CLINICAL OUTCOMES:

Increased Hb levels

Decreased vaso-occlusion

HYPOTHESIS #2:

PKR activation increases ATP,

promoting RBC repair/health and

reducing hemolysis

HYPOTHESIS #1:

PKR activation decreases 2,3-DPG,

reducing HbS polymerization

and sickling

Hb=hemoglobin; deoxyHb=deoxygenated Hb ; PKR= pyruvate kinase-R; 2,3-DPG=2,3-diphosphoglycerate; ADP=adenosine diphosphate; ATP=adenosine triphosphate; PEP=phosphoenolpyruvate

Brown RC, et al. Presented at: EHA 2021 Virtual Meeting; Jun 9-17, 2021 [E-Poster EP1202].

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Etavopivat Phase 1 Study: Design and StatusRandomized, Placebo-controlled, Multi-center (NCT03815695)

Healthy

volunteers3

(N=90]

Patients with

SCD

Single Ascending Dose (Completed)

Randomization vs placebo

700 mg

300 mg

once daily

Single Dose4 (Completed, N=7)

Randomization vs placebo

Multiple Ascending Dose (Completed, N=20)

Etavopivat vs placebo, 2 weeks of treatment

600 mg

once daily

700 mg400 mg200 mg 100 mg BID

Multiple Ascending Dose (Completed)

Randomization vs placebo, 2 weeks of treatment

200 mg BID 300 mg BID1000 mg 400 mg QD

Open-label Extension (Ongoing, N = up to 20 )

Etavopivat, 12 weeks of treatment

400 mg

once daily

EHA 2021Patients with SCD treated with etavopivat (300 mg and 600 mg) once daily x 2 weeks (data as of May 10, 2021)

Patients with SCD treated with etavopivat 400 mg once daily x 12 week; initial results* (data as of May 24, 2021)

SCD=sickle cell disease

Brown RC, et al. Presented at: EHA 2021 Virtual Meeting; Jun 9-17, 2021 [E-Poster EP1202

* Initial results for patients who received etavopivat 400 mg once daily for at least 2 weeks: patients had a median of 10 weeks (mean of 8 weeks) of etavopivat treatment

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Parameter,

Mean (range) or n (%)

Etavopivat or Placebo once daily, 2 weeks Etavopivat once daily, 12 weeks

300 mg (N=10) 600 mg (N=10) 400 mg (N=10)

Age, years 28.5 (19, 43) 24.0 (17, 64) 26.5 (17, 41)

Male 3 (30%) 3 (30%) 3 (30%)

Genotype

HbSS 9 (90%) 8 (80%) 10 (100%)

HbSβ+-thalassemia 1 (10%) 1 (10%) 0

HbSC 0 1 (10%) 0

HU therapy 7 (70%) 9 (90%) 10 (100%)

Hb, g/dL 8.7 (6.9, 10.1) 8.6 (7.3, 10.2) 8.8 (7.7, 10.0)

% HbS 82.0 (67.0, 92.9) 83.5 (78.2, 92.7) 81.8 (72.6, 92.7)#

% HbF 11.5 (3.5, 20.1) 12.0 (4.4, 19.2) 13.6 (4.4, 23.0)#

MCV, fL 107.1 (75.0, 131.5) 108.2 (68.5, 129.6) 110.4 (91.0, 122.7)

ARC, 109/L 249.1 (125.6, 329.3) 250.6 (29.4, 366.0) 246.6 (78.3, 363.2)

Indirect bilirubin, mg/dL 3.05 (0.5, 10.5) 2.27 (0.7, 5.0) 2.24 (0.9, 5.2)

LDH, U/L 398.2 (180, 699) 419.8 (251, 683) 424.6 (186, 683)

% F cells 41.7 (16.4, 67.2) 43.3 (13.3, 64.8) 54.9 (22.3, 76.9)

Etavopivat Phase 1 Study: Patient Baseline Characteristics

ARC=absolute reticulocyte count; Hb=hemoglobin; HbF=fetal hemoglobin; HbS=sickle hemoglobin; HU=hydroxyurea; LDH=Lactate dehydrogenase; MCV= mean corpuscular volume


#n=8

15

Etavopivat 300 mg and 600 mg Once Daily for 2 Weeks:Comparable Decrease in 2,3-DPG and Increase in ATP

1.0 1.5 2.0

1

10

100

1000

14 15 16 17 18

Time (day)

Eta

vo

piv

at

(ng

/mL

)

300 mg QD 600 mg QD

1 5 9 13 17 21

2000

4000

6000

8000

Time (day)

2,3

-DP

G (

g/g

Hb

)

300 mg QD

Line: mean

Shaded area: 5th

-95th

range

600 mg QD

1 5 9 13 17 21

1000

2000

3000

4000

5000

Time (day)

AT

P (

g/g

Hb

)

300 mg QD

Line: mean

Shaded area: 5th-95th range

600 mg QD

• Dose-proportional PK and comparable PD responses (↓ 2,3-DPG and ↑ ATP) with etavopivat 600 mg or 300 mg once

daily for 2 weeks

• Confirms prior studies in healthy volunteers predicting doses ≥ 400 mg once daily would maximize PD

• Overlapping PD results support combined analyses of the 300 mg and 600 mg dose cohorts

Results support etavopivat 400 mg once daily as the maximum dose in the Phase 2/3

pivotal trial (the Hibiscus Study)PK=Pharmacokinetics; PD=Pharmacodynamics


Hibiscus Study (NCT04624659)

Data as of May 10, 2021

ATP2,3-DPGEtavopivat

16

Parameters Placebo

(N=4)

Etavopivat 300 mg

Once daily, 2 weeks

(N=8)

Etavopivat 600 mg

Once daily, 2 weeks

(N=8)

AE, n (%)

Any AE 1 (25.0) 7 (87.5) 6 (75.0)

Related to study drug 0 2 (25.0) 0

Any SAE 0 0 1 (12.5)

Related to study drug 0 0 0

AEs by severity

Grade 1

Grade 2

Grade 3

Grade 4

3

2

1

1

6

7

0

0

7

7

1

0

Etavopivat Once Daily for 2 Weeks was Well-tolerated:Comparable Safety Profile with 300 mg or 600 mg Once Daily

AE=adverse event; SAE=serious AE


Hibiscus Study (NCT04624659)

Favorable tolerability profile, most common AEs (≥ 3 pts): Sickle cell anemia pain events (n=5), headache (n=4), and nausea (n=3)

Etavopivat was well-tolerated up to 600 mg once daily,

which is 150% of the Hibiscus Study maximum dose


17

Etavopivat 300 mg or 600 mg Once Daily for 2 Weeks Significantly Improves Hematologic and Hemolytic Parameters

EOT=end of treatment; Hb=hemoglobin; LDH=lactate dehydrogenase



• In patients treated with etavopivat and evaluable for response (n=15):

o 73% (11/15) achieved Hb ≥ 1 g/dL over baseline at EOT (mean ↑ 1.2 g/dL; p<0.002)

o 100% (15/15) had ↓ absolute reticulocytes relative to baseline at EOT (mean ↓ 47%; p<0.001)

o 73% (11/15) had ↓ LDH levels over baseline at EOT (mean ↓ 19%; p<0.07)

o 93% (14/15) had ↓ indirect bilirubin levels over baseline at EOT (mean ↓ 38%; p<0.002)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

-4

-2

0

2

4

-80

-60

-40

-20

0

20

40

60

80

Hb

Ab

so

lute

Ch

an

ge (

g/d

L) A

bso

lute

Re

ticu

locy

tes

(% C

ha

ng

e)

Hemoglobin Reticulocytes

Treated Patient #

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15-80

-60

-40

-20

0

20

40

60

80

(% C

ha

ng

e)

Treated Patient #

LDH Bilirubin

18

Etavopivat Once Daily up to 12 Weeks was Well-tolerated:Safety Profile Consistent with Underlying Disease

AE, n (%)

Etavopivat 400 mg once daily up to 12 weeks1

All Grades (≥ 10%)N=8

Grade ≥ 3N=8

Acute chest syndrome (ACS) 1 (12.5) 1 (12.5)

Blood CPK abnormal 1 (12.5) 1 (12.5)

Deep Vein Thrombosis (DVT) 1 (12.5) 1 (12.5)

Fatigue 1 (12.5) 0

Headache 1 (12.5) 0

Lymphadenopathy 1 (12.5) 0

Menorrhagia 1 (12.5) 0

Muscle strain 1 (12.5) 0

Neutropenia 1 (12.5) 0

Peripheral swelling 1 (12.5) 0

Priapism 1 (12.5) 0

Sickle cell anemia with crisis (VOC) 1 (12.5) 1 (12.5)

Serious AEs:

1 patient (unrelated): ACS and

VOC after EOT, precipitated by

upper respiratory infection

symptoms (non-COVID)

1 patient (possibly related): left

femoral vein DVT on day 14 of

treatment

1AEs in patients who received etavopivat 400 mg once daily for at least 2 weeks (median 10 weeks; mean 8 weeks)

AE=adverse event; EOT=end of treatment



19

Etavopivat 400 mg Once Daily up to 12 Weeks:Improved and Sustained Hemoglobin Increase

Responder Parameter N=8

Maximal Hb increase, mean (SD),

g/dL1.5 (0.4)

Hb increase > 1 g/dL, n (%) 7 (88)

Maximal Hb increase in subjects with

> 1 g/dL response, mean (SD), g/dL1.6 (0.3)

BLW

k 2W

k 4W

k 6W

k 8

Wk 1

0

Wk 1

2

8

10

12

Hb

(g

/dL

)

Mean

n=8 8 6 5 5 4 4

Hemoglobin

Hb=hemoglobin; BL=baseline; Wk=week


Patients who received etavopivat 400 mg once daily for at least 2 weeks:

patients had a median of 10 weeks (mean of 8 weeks) of etavopivat

treatment


20

Etavopivat 400 mg Once Daily up to 12 Weeks:Decreased and Sustained RBC Turnover and Hemolysis

LDH=lactate dehydrogenase; BL=baseline; wk=week



Reticulocytes LDHBilirubin

BL

Wk

2

Wk

4

Wk

6

Wk

8

Wk

10

Wk

12

0

100

200

300

400

500

Ab

so

lute

Reti

cu

loc

yte

s

(10

9/L

)

Mean

ULN

n=8 8 6 5 5 4 4

BL

Wk

2

Wk

4

Wk

6

Wk

8

Wk

10

Wk

12

0

200

400

600

800

LD

H (

U/L

)

Mean

ULN

n=8 8 6 5 5 4 4

BL

Wk

2

Wk

4

Wk

6

Wk

8

Wk

10

Wk

12

0

2

4

6

Bilir

ub

in (

mg

/dL

)

Mean

ULN

n=8 7 6 5 5 4 4

Trend towards normalization of reticulocytes, bilirubin and LDH by 12 weeks

Patients who received etavopivat 400 mg once daily for at least 2 weeks: patients had a median of 10 weeks (mean of 8 weeks) of etavopivat treatment

21

Etavopivat 400 Mg Once Daily for 12 Weeks: Reduction in Systemic Markers of Sickle Cell Pathophysiology

Lab Test Normal rangePatients

(n)Baseline

Median % Maximum

Change (range)P-value

Tissue hypoxia Erythropoietin 2.6 – 18.5 mIU/mL 4 140.3 (106.7, 157.1) -42.3 (-66.6, -7.3) 0.1250

HypercoagulabilityProthrombin 1.2 87 – 325 pmol/L 7 617 (386, 4900) -61.0 (-86.5, 10.2) 0.0313

D-dimer < 0.50 mcg/mL 6 3.56 (2.08, 5.9) -51.9 (-94.3, 25.5) 0.0625

Inflammation TNF-a 0.56-1.40 pg/mL 7 1.34 (0.79, 2.2) -26.1 (-69.4, 0.9) 0.0313

Patients receiving etavopivat 400 mg daily for up to 12 weeks were assessed for systemic markers of

sickle cell pathophysiology including:

• Intravascular hemolysis: Indirect bilirubin and LDH

• Tissue hypoxia: erythropoietin levels

• Hypercoagulability: Prothrombin 1.2, TAT complexes and D-dimer

• Inflammation: ferritin, CRP, TNF-a, IL-1b, IL-8 and IL-6

Data as of June 6, 2021

22

0 20 40 60 80 100 120 140

0.0

0.2

0.4

0.6

pO2 (mmHg)

Elo

ng

ati

on

In

dex

0 50 100 150 200 250 300 350 400 450 500

0.0

0.2

0.4

0.6

Osmolality (mOsm/kg)

Elo

ng

ati

on

In

dex

EImax

0 50 100 150

0

25

50

75

100

pO2 (mmHg)

% O

xyh

em

og

lob

in

Pre EOT EOS

P50 29.7 25.2 32

Pre EOT EOS

POS

EImax

40.6 30.7 40.8

0.32 0.52 0.49

Pre EOT EOS

EImax 0.42 0.54 0.52

O2 Affinity Curve Osmoscan

Healthy RBC: SCD RBC (Pre-dose): SCD RBC EOT (Day 15): SCD RBC EOS (Day 21):

Oxygenscan

POSEImax

Patient with SCD before and after 2 wks of etavopivat and after a 1-wk washout

EOT = end of treatment; EOS = end of study; POS = point of sickling

Etavopivat Improved the Functional Health of Sickle RBCs

• Sickle RBCs from patients who received etavopivat for 2 wks had an assessment of functional health by O2 affinity, O2 gradient, or an

osmotic gradient

• A representative analysis from 1 patient performed pre-treatment, at EOT, and up to 1 wk after completion of etavopivat treatment (EOS) is shown

• Collectively, results from 14 patients analyzed show that etavopivat-treated sickle RBCs have significantly increased Hb-O2 affinity

(p=0.0001), significant shift in the POS (p=0.004) and significantly improved deformability (EImax) by oxygenscan (p=0.025) or

osmoscan (p=0.037)

23

Improvement in Sickle RBC Deformability May Persist after Etavopivat Treatment Discontinuation

Oxygenscans performed at the indicated timepoints showed:

• Improved RBC deformability (EImax) after 2 weeks of

etavopivat at both doses

• EImax returning to pre-treatment level during WO between

etavopivat treatments

• Improved RBC deformability maintained for at least 4

weeks after WO of etavopivat 400 mg once daily

Pre

-dose

D 1

4

1 W

k W

O

Pre

-dose

(3 W

k W

O)

D 1

4

12 W

k

1 W

k W

O

2 W

k W

O

4 W

k W

O

0.40

0.45

0.50

0.55

0.60

Elo

ng

ati

on

In

dex (

EI m

ax)

600 mg 400 mg

HEALTHY RBC EImax

Etavopivat-treated patient:

600 mg once daily for 2 wks, followed by 3 wks WO

then etavopivat 400 mg once daily for 12 wks, followed by 4 wks WO

WO=washout; wk=week



24

Etavopivat Improved RBC Functions Important for Metabolic Health, Adhesion, and Survival

Pre-dose Day 15

0.9

1.0

1.1

1.2

1.3

1.4

1.5

Fo

ld D

iffe

ren

ce

0.0010p=

Pre-dose Day 15

0.9

1.0

1.1

1.2

1.3

1.4

Fo

ld D

iffe

ren

ce

0.0037p=

Pre-dose Day 15

0.8

1.0

1.2

1.4

1.6

1.8

Fo

ld D

iffe

ren

ce

0.0002p=

Pre-dose Day 15

0.0

0.5

1.0

1.5

Fo

ld D

iffe

ren

ce

0.0078p=

PS Expression

n=11 n=13n=13 n=8

A: B: C: D:GSH Reductase ActivitySOD ActivityPKR Activity

RBCs from patients with SCD treated with etavopivat 300 mg or 600 mg QD for 2 wks showed:

• ↑ PKR activity over baseline, comparable for 300 mg and 600 mg dose cohorts (A)

• ↑ in RBC antioxidant capacity and improved RBC redox potential (B, C)

• ↓ PS expression on the sickle RBC membrane suggesting improved membrane repair (D)

PKR = RBC Pyruvate Kinase; SOD = super-oxide dismutase; GSH = glutathione; PS = phosphatidyl serine


David Cook, Ph.D.SVP, CHIEF SCIENTIFIC OFFICER

25

Etavopivat MOA and Novel Biology from Phase 1 Data

26

27

Etavopivat: Results Supporting Improved RBC Functional Health

Decreased Levels of 2,3-DPG

Increased Levels of ATP

Decreased Hemolysis

Improved RBC Hydration and Deformability

Decreased PS on the RBC Membrane

Increased Antioxidant Enzyme Activity

Decreased procoagulant & proinflammatory biomarkers

Reduced RBC sickling

Increased RBC energy reserves

Increased RBC lifespan and reduced inflammation

Increased ability to transit small vessels

Reduced membrane damage

Reduced protein, membrane & blood vessel damage (vasculopathy)

1

2

3

4

5

6

PKR= pyruvate kinase-R; 2,3-DPG=2,3-diphosphoglycerate; ATP=adenosine triphosphate; PS=phosphatidyl serine

7 Reduced potential for vascular activation and vaso-occlusion

28

Sickle Cell Disease, although Driven by a Single Mutation, is

Complex and Multifactorial

SicklingHemolysis

Free Heme

• Pain Crisis• Stroke• Infection

• Organ Damage• Early Death

HbS

Polymerization

Activation of Innate Immune

Pathways

Vaso-occlusion

Activation of Vascular Endotheliumand Vaso-constriction

Ischemia Reperfusion Injury

modified from Gladwin, Kato, Novelli 2021

29

Decreased 2,3-DPG: Reduced RBC Sickling

1 5 9 13 17 21

2000

4000

6000

8000

Time (day)

2,3

-DP

G (

g/g

Hb

)

300 mg QD

line: PopPKPD mean

shaded area: 5th-95th range

600 mg QD

Etavopivat consistently decreases 2,3-DPG

+ DPG / −O2

− DPG / +O2

Decreased 2,3-DPG

increases oxygen affinity

and reduces polymerization

and sickling• Pain Crisis• Stroke• Infection


HbS

Polymerization

Innate Immune Activation

Vaso-occlusionVascular Activation

and Vaso-constriction

1

1 1

2,3-DPG=2,3-diphosphoglycerate


30

Increased ATP: Increased RBC Energy Charge

Etavopivat consistently increases ATP and PKR activity

↑ ATP essential for membrane repair, ionic homeostasis, hydration and deformability



HbS

Polymerization




22

1 5 9 13 17 21

1000

2000

3000

4000

5000

Time (day)

AT

P (

g/g

Hb

)

300 mg QD

line: PopPKPD mean

shaded area: 5th-95th range

600 mg QD

2

Pre-dose Day 15

0.9

1.0

1.1

1.2

1.3

1.4

1.5

Fo

ld D

ifferen

ce

0.0010p=

PKR ActivityATP

ATP=adenosine triphosphate; PKR=pyruvate kinase-R


31

Decreased Hemolysis: Increased RBC lifespan and ReducedInflammation

Etavopivat ↑ Hb and ↓ reticulocytes demonstrating increased RBC lifespan



HbS

Polymerization




Etavopivat ↓ LDH and ↓ bilirubin demonstrating decreased hemolysis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15-4

-2

0

2

4

-80

-60

-40

-20

0

20

40

60

80

Hb

Ab

so

lute

Ch

an

ge (

g/d

L) A

bso

lute

Retic

ulo

cyte

s

(% C

ha

ng

e)

Hemoglobin Reticulocytes

Treated Patient #

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15-80

-60

-40

-20

0

20

40

60

80

(% C

ha

ng

e)

Treated Patient #

LDH Bilirubin

3

3

3

LDH=lactate dehydrogenase


32

Improved RBC Deformability and Hydration: Increased Ability to Transit Small Vessels



HbS

Polymerization




4

4

Etavopivat results in higher baseline deformability as measured by Oxygenscan

0 20 40 60 80 100 120 140

0.0

0.2

0.4

0.6

pO2 (mmHg)

Elo

ng

ati

on

In

dex

Defo

rmabili

ty (

EI u

nits

)

Oxygen Pressure (mmHg)

Deformability is durable up to 4 weeks after 12-weeks treatment

Pre

-dose

D14

1 w W

O

Pre

-dose

(3w W

O) D

14

12

w

1w W

O

2w W

O

4w W

O

0.40

0.45

0.50

0.55

0.60

EI m

ax

600 mg 400 mg

HEALTHY RBC EImax

Defo

rmabili

ty (

EI u

nits

)

Etavopivat improves ability to maintain ionic gradients and intracellular hydration as measured by Osmoscan

0 50 100 150 200 250 300 350 400 450 500

0.0

0.2

0.4

0.6


Elo

ng

ati

on

In

dex

Defo

rmabili

ty (

EI u

nits

)


Enabled by ATP and improved anti-oxidant activity

4

ATP=adenosine triphosphate


33

Decreased PS: Reduced Membrane Damage

Repeated sickling results in PS on the outer RBC membrane

Etavopivat decreases PS expression on RBC outer membrane



HbS

Polymerization




5

5

Pre-Dose Day 15

0.0

0.5

1.0

1.5

Fo

ld d

iffe

ren

ce

0.0078p=

PS Expression

PSATP ADPFlippase

PS accelerates RBC clearance by the

macrophages in spleen and liver

ATP repairs this damage by

activating flippase, which flips PS

back to the inner RBC membrane

5

PS=phosphatidyl serine; ATP=adenosine triphosphate; ADP=adenosine diphosphate;


34

Etavopivat increases activity of SOD and GSH Reductase



HbS

Polymerization




↑ SOD and GSH reductase

aid in elimination of toxic

reactive oxygen species from

sickle RBC

This reduces damage to

membranes and proteins

6

6

Pre-Dose Day 15

0.9

1.0

1.1

1.2

1.3

1.4

Fo

ld d

iffe

ren

ce

0.0037p=

Pre-Dose Day 15

0.8

1.0

1.2

1.4

1.6

1.8

Fo

ld d

iffe

ren

ce

0.0002p=

GSH ReductaseSOD

02

SOD

H202 + H20

catalase

02 + H20 02 + H20

superoxide

GSH

GSSG

GSHReductase

6 Increased Anti-oxidant Enzyme Activity: Reduced Protein, Membrane and Blood Vessel Damage

SOD = super-oxide dismutase; GSH = glutathione


35

Decreased Pro-inflammatory and Pro-coagulant Markers: Reduced Potential for Vascular Activation and Vaso-occlusion



HbS

Polymerization




7 7

7

ATP=adenosine triphosphate


7

Cytokines (e.g. TNF-a) activate blood coagulation and adhesins on neutrophils, platelets and vascular endothelium

In narrow vessels, sickled RBCs bind these activated cells and cause vaso-occlusion

36

• Etavopivat-mediated activation of glycolysis results in:

• Reduced RBC sickling – the key to all downstream pathology

• Decreased hemolysis – a driver of inflammation & vascular activation

• Improved RBC deformability & hydration – reducing vaso-occulsion

• Reduced membrane damage – reducing RBC adhesion and clearance

• Protection from reactive oxygen species – protects both proteins and membranes

• Reduced pro-inflammatory and pro-coagulant biomarkers – demonstrating systemic

effects of etavopivat

• These data suggest etavopivat may improve the overall functional health of sickle RBCs and

reduce the risk of vaso-occlusive events, thus altering the pathophysiology of SCD

Etavopivat-mediated PKR Activation Demonstrates Potential to Improve RBC Health via Multimodal MOA

37

Q&A

Frank LeePRESIDENT, CHIEF EXECUTIVE OFFICER,

AND DIRECTOR

38

Summary – Etavopivat Phase I Results Support Hibiscus Study Design And Potential as Foundational Therapy in SCD

► Rigorous Phase I study

► Etavopivat once daily

• A favorable tolerability profile in patients with SCD - supporting a safety margin for maximum dose

selected for Hibiscus Study ( Phase 2/3 )

• Initial results from the open-label 12-week dose cohort indicate a sustained hemoglobin increase (>1 g/dL)

in 88% of patients for up to 12 weeks with a trend toward normalization in markers of hemolysis

• Improved sickle RBC deformability sustained for up to 4 weeks after treatment discontinuation

► Improved RBC functions important for metabolic health, adhesion, and survival

► Improved systemic markers of SCD pathophysiology beyond metabolic pathway

39

Thank you to our patients,

caregivers, and investigators

european hematology association

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